Discovery and Characterization of Radiation Mitigator Yel002

The possibility of a radiation disaster from a nuclear detonation or accident has existed for over 50 years. This concern has been the the dominating influence of much of the basic research in radiobiology in the 1950-60s. The recent Fukushima accident was yet another reminder that of the dire need to develop novel therapies against radiation-induced toxicities. This dissertation describes our efforts to develop the novel radiation mitigator Yel002 starting from a phenotypic yeast-based DEL screen to the elucidation of its potential mechanism of action. Yel002 is small, biologically active, drug-like molecule that mitigates on average 75% of deaths in mice following an LD100/30 irradiation when administered at 24, 48, 72, 96, and 120 hours after the exposure. Treatment with Yel002 following IR accelerates the recovery of the hematopoietic and immune systems possibly by preventing radiation-induced cell death and senescence of bone marrow stem cells and progenitors. Toxicity has not been observed in either in vitro or in vivo administrations. Overall, the Yel002 compound has much potential to become a stockpile therapy for radiation-induced lethality and cancer: it is highly effective when administered up to 24 hours post exposure, it reduces radiation-induce sequelae such as leukemia and appears to have an acceptable toxicity profile.